We propose to create what will be the largest catalogue of DNA sequence variation in phenotyped samples and to pioneer the application of this depth and scale of data to the analysis of key cardiovascular phenotypes. We propose to do this by (1) performing comprehensive sequencing (on a genome- or exome-wide scale, as determined in collaboration with the Project Steering Committee) in each of 10,000 phenotyped samples;(2) rapidly genotyping an initial set of novel variants in 20,000 additional samples, and (3) making available to the research community raw data, annotated variants, and a framework for variant detection, validation and association to phenotypes. The ultimate goal of this project is to create a data and analytic resource that will lay the groundwork for subsequent interrogation of the full spectrum of allele frequency variation in a wide array of cardiovascular phenotypes for many subsequent years. PUBLIC HEALTH RELEVANCE: The proposed project aims to comprehensively describe DNA sequence variation in the most functionally relevant and interpretable portion of the human genome (the exome), and to enable downstream association of these findings to the vast collection of cardiovascular disease and clinical phenotypes measured in NHLBI cohort samples. This will make possible deep inspection of known risk loci and discovery of many new loci previously missed in mapping studies - leading to new biologic hypothesis, new drug targets, and improved clinical prediction.